Immune Checkpoint Inhibitor-Induced Pneumonitis in Patients With Non-Small Cell Lung Cancer and Preexisting Interstitial Lung Diseases: Really Mild and Easily Manageable?

Abstract

We have read with interest the study by Zhang et al1Zhang M. Fan Y. Nie L. Wang G. Sun K. Cheng Y. Clinical outcomes of immune checkpoint inhibitor therapy in patients with advanced non-small cell lung cancer and preexisting interstitial lung diseases: a systematic review and meta-analysis.Chest. 2022; 161: 1675-1686Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar in CHEST (June 2022). This meta-analysis included three small prospective and seven retrospective studies, and concluded that, although caution is warranted because of the high incidence of pneumonitis in patients with interstitial lung disease (ILD), most pneumonitis is mild and easily manageable, and no association exists between usual interstitial pneumonia (UIP) patterns and pneumonitis risk. For patients with non-small cell lung cancer and ILD, and who have a poor prognosis, immune checkpoint inhibitor therapy remains a promising treatment option with the potential for long-term survival. However, as authors of a phase 2 study of atezolizumab (AMBITIOUS), which was terminated because of the high incidence of severe pneumonitis and is included in this meta-analysis,2Ikeda S. Kato T. Kenmotsu H. et al.A phase 2 study of atezolizumab for pretreated NSCLC with idiopathic interstitial pneumonitis.J Thorac Oncol. 2020; 15: 1935-1942Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar we are concerned that some of the authors’ interpretations may be misleading to readers for the following three reasons. First, studies included in this meta-analysis were few and too disparate in quality, with a mix of prospective single-arm interventional studies and retrospective case-control studies, and even the prospective studies differed greatly in their ILD selection criteria. Although sensitivity analyses and assessment of publication bias were conducted, it may be difficult to draw any definitive conclusions from this meta-analysis. Second, it is still unclear whether most pneumonitis is truly mild and easily manageable. In our phase 2 AMBITIOUS study, 23.5% developed grade ≥ 3 pneumonitis, of which 25% were fatal, and another 25% had severe respiratory failure requiring noninvasive positive-pressure ventilation.2Ikeda S. Kato T. Kenmotsu H. et al.A phase 2 study of atezolizumab for pretreated NSCLC with idiopathic interstitial pneumonitis.J Thorac Oncol. 2020; 15: 1935-1942Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar Third, three prospective studies implicated an association between UIP patterns and a high incidence of severe pneumonitis. In the AMBITIOUS study, 57% of patients with a UIP pattern with honeycomb lung had grade ≥ 3 pneumonitis, whereas only 10% of patients with a non-UIP pattern had grade 1 pneumonitis.2Ikeda S. Kato T. Kenmotsu H. et al.A phase 2 study of atezolizumab for pretreated NSCLC with idiopathic interstitial pneumonitis.J Thorac Oncol. 2020; 15: 1935-1942Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar Meanwhile, two prospective studies of nivolumab with a low pneumonitis incidence excluded patients with a UIP pattern.3Fujimoto D. Morimoto T. Ito J. et al.A pilot trial of nivolumab treatment for advanced non-small cell lung cancer patients with mild idiopathic interstitial pneumonia.Lung Cancer. 2017; 111: 1-5Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar,4Fujimoto D. Yomota M. Sekine A. et al.Nivolumab for advanced non-small cell lung cancer patients with mild idiopathic interstitial pneumonia: a multicenter, open-label single-arm phase II trial.Lung Cancer. 2019; 134: 274-278Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar Furthermore, ILDs were centrally reviewed by radiologists in the AMBITIOUS study, whereas in the retrospective study cited in the author discussion of the relationship between UIP patterns and pneumonitis incidence, ILDs were reviewed only by pulmonologists.5Tasaka Y. Honda T. Nishiyama N. et al.Non-inferior clinical outcomes of immune checkpoint inhibitors in non-small cell lung cancer patients with interstitial lung disease.Lung Cancer. 2021; 155: 120-126Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar Determining honeycomb lung is so difficult that even experienced radiologists can disagree. Accordingly, we believe that immune checkpoint inhibitor-induced pneumonitis in patients with non-small cell lung cancer and ILD is not always mild and manageable, and on the basis of the existing data, more prudence is required at least for patients with UIP patterns. Author contributions: S. I. had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. S. I.: formal analysis, investigation, writing (original draft). T. M.: formal analysis, investigation, and writing (review and editing). T. K.: investigation, writing (review and editing). T. O.: investigation, writing (review and editing). H. O.: investigation, and writing (review and editing). Financial/nonfinancial disclosures: The authors have reported to CHEST the following: S. I. received grants and honoraria for lectures from Chugai; grants and honoraria for lectures from AstraZeneca; and honoraria for lectures from Boehringer Ingelheim, Ono, Taiho, Bristol Myers Squibb, Eli Lilly, and Pfizer. T. K. received grants and honoraria for lectures from Chugai; honoraria for lectures and as a member of the advisory board from AbbVie, Amgen, AstraZeneca, Eli Lilly, Merck Biopharma, MSD, Ono, Pfizer, and Taiho; honoraria for lectures from Boehringer Ingelheim, Bristol Myers Squibb, Novartis, Daiichi-Sankyo, F. Hoffmann-La Roche, Shionogi, and Sumitomo Dainippon; and honoraria as a member of the advisory board from Nippon Kayaku, Nitto Denko, and Takeda. H. O. received grants and honoraria for lectures from Bristol Myers Squibb and Chugai; grants from Taiho, Astellas, Eli Lilly, and Merck; and honoraria for lectures from MSD, AstraZeneca, Kyorin, Boehringer Ingelheim, and Novartis. T. O. received honoraria for lectures from Shionogi, Boehringer Ingelheim, and Eisai. None declared (T. M.). Other contributions: The authors thank the patients and their families, the Thoracic Oncology Research Group data center staff, and all the investigators who participated in the TORG1936/AMBITIOUS study. Clinical Outcomes of Immune Checkpoint Inhibitor Therapy in Patients With Advanced Non-small Cell Lung Cancer and Preexisting Interstitial Lung Diseases: A Systematic Review and Meta-analysisCHESTVol. 161Issue 6PreviewProgrammed cell death protein 1/programmed cell death ligand 1 inhibitors had favorable efficacy in NSCLC with preexisting ILD. CIP is frequent in patients with preexisting ILD who receive ICI therapy but is often mild and easily manageable. Clinicians should be cautious when using ICIs in patients with preexisting ILD. Full-Text PDF ResponseCHESTVol. 162Issue 1PreviewWe thank Drs Ikeda and colleagues for their comments on our publication.1 Full-Text PDF